Salmaso Stefano, Bersani Sara, Semenzato Alessandra, Caliceti Paolo
Department of Pharmaceutical Sciences, University of Padova, Padova, Italy.
J Drug Target. 2007 Jul;15(6):379-90. doi: 10.1080/10611860701349752.
A new cyclodextrin-based carrier for active targeting of low soluble and degradable drugs has been synthesized and characterized. Beta-cyclodextrins were first reacted with excess hexamethylene diisocyanate and the resulting CD-(C6-NCO)5 derivative was reacted with 700 Da diamino-PEG to yield CD-(C6-PEG-NH2)5. About one out of five free amino groups of PEG were functionalised with folic acid (FA) as a tumour targeting moiety. The chemical structures of the intermediates as well as the final product, CD-(C6-PEG)5-FA, were characterized by 1H and 13C NMR, reverse phase and gel permeation chromatography, and UV-Vis spectroscopy. After modification, the haemolytic activity of beta-cyclodextrins decreased by about 70%. In the presence of the new carrier, the beta-estradiol solubility increased by more than 300 fold and the chlorambucil degradation rate decreased by 50-60%. CD-(C6-PEG)5-FA formed an inclusion complex with curcumin displaying an association constant of 954,732 M(-1). The new carrier increased the curcumin solubility by about 3200 fold as compared to native beta-cyclodextrins and reduced its degradation rate at pH 6.5 and 7.2 by 10 and 45 fold, respectively. FA receptor-overexpressing human nasopharyngeal tumour KB cell lines and non-folic acid receptor-expressing human breast cancer MCF7 cells were used to evaluate the targeting properties of the new drug delivery system. The in vitro studies demonstrate that the new carrier possesses potential selectivity for the folate receptor-overexpressing tumour cells as ED50 values of 52 microM, 58 microM and 21 microM were obtained with curcumin-loaded CD-(C6-PEG-NH2)5, curcumin in foetal serum medium and CD-(C6-PEG)5-FA, respectively.
一种用于低溶解性和可降解药物主动靶向的新型环糊精基载体已被合成并表征。首先使β-环糊精与过量的六亚甲基二异氰酸酯反应，然后将所得的CD-(C6-NCO)5衍生物与700 Da的二氨基聚乙二醇反应，得到CD-(C6-PEG-NH2)5。聚乙二醇的约五分之一游离氨基用叶酸（FA）作为肿瘤靶向部分进行功能化修饰。通过1H和13C核磁共振、反相和凝胶渗透色谱以及紫外可见光谱对中间体以及最终产物CD-(C6-PEG)5-FA的化学结构进行了表征。修饰后，β-环糊精的溶血活性降低了约70%。在新载体存在下，β-雌二醇的溶解度增加了300多倍，苯丁酸氮芥的降解率降低了50 - 60%。CD-(C6-PEG)5-FA与姜黄素形成了包合物，其缔合常数为954,732 M(-1)。与天然β-环糊精相比，新载体使姜黄素的溶解度增加了约3200倍，并分别在pH 6.5和7.2时将其降解率降低了10倍和45倍。使用叶酸受体过表达的人鼻咽癌KB细胞系和不表达叶酸受体的人乳腺癌MCF7细胞来评估新药物递送系统的靶向特性。体外研究表明，新载体对叶酸受体过表达的肿瘤细胞具有潜在的选择性，负载姜黄素的CD-(C6-PEG-NH2)5、胎牛血清培养基中的姜黄素和CD-(C6-PEG)5-FA的半数有效浓度（ED50）分别为52 microM、58 microM和21 microM。
